Despite the availability of several, effective pharmacotherapies, opioid abuse continues to pose a major public health problem worldwide. Currently available pharmacotherapies are effective in only some patients and the need continues for new and better treatments for opioid abuse. Prior research under this grant developed discrimination procedures for studying opioid dependence and withdrawal. Studies in this application will use those, and other, procedures to examine the development of dependence to novel opioids and to test hypotheses regarding drug interactions and the possible attenuation of dependence and withdrawal. Specific Aim I will determine whether opioid or non-opioid tolerance or dependence develops during treatment with the novel fentanyl derivative mirfentanil. Specific Aim II will examine the role of P450 enzymes in the morphine-like effects of codeine and oxycodone and determine whether other drugs (N-methyl-D-aspartate antagonists [NMDA] and nitric oxide synthase [NOS] inhibitors) modify opioid tolerance and dependence. These studies will compare methadone and its stereo isomers because these opioids also have effects at NMDA receptors. Upon completion of a study on LAAM dependence and withdrawal, studies under Specific Aim III will test the hypothesis that variations among mu opioids in their effects on receptor internalization and G-protein coupling will be expressed as differences in tolerance and dependence. Naltrexone will be established as a discriminative stimulus in untreated monkeys (Specific Aim IV) to begin a characterization of behavioral effects that might be important to the therapeutic utility of these drugs (e.g., alcohol abuse). Specific Aim V will use pigeons to study efficacy and selectivity differences among opioids and also to determine whether hypothesized interactions between different opioid receptors has functional consequences for drug dependence and withdrawal. The procedures developed under this grant provide a unique set of conditions for evaluating the effects of other drugs on behaviors related to and predictive of the subjective effects of withdrawal in humans.